Improved and more sensitive techniques for detecting the range of HIV-induced neurocognitive impairment (NCI) [asymptomatic neurocognitive impairment (ANI), mild neurocognitive disorder (MND) or HIV-associated dementia (HAD)] document NCI as a major co-morbidity of HIV-1 (HIV) infection. Building on the confluence of new information showing that CD14-positive Monocyte-associated HIV DNA Viral Load (CD14MADVL) correlates with NCI, coupled to unpublished data from co-investigator S. Gartner documenting a highly distinct virus in CD14 positive monocyte, the current proposal targets in depth pathogenesis research of the virus in this compartment drawing from a unique prospective cohort of treatment naive patients recruited from a large Nigerian PEPFAR program. The conceptual framework for this project draws from the well established fact that HIV enters the brain primarily via the trafficking of infected blood monocytes and virus in this compartment provides a window for understanding the pathogenesis of NCI without direct access to brain tissue. Our preliminary studies document capacity to enroll and detect large numbers of treatment naive patients with NCI, maintain them in prospective follow up and perform in depth laboratory analysis of the virus from monocytes, CD-14 negative mononuclear cells, plasma and CSF. The central hypothesis of this grant application is that the previously reported correlation between severity of NCI and CD14MADVL is linked to a distinctive pattern of viral quasi-species in this compartment (unpublished preliminary data) and that detailed analysis of viral motifs among the quasi-species from this compartment compared to non-monocyte HIV DNA and plasma viral RNA offer promise for identifying signature patterns that will inform NCI pathogenesis. This hypothesis will be addressed in two aims:
Aim 1 - Classification of NCI and correlation with CD14MADVL in cross sectional study and longitudinally, and Aim 2 - Detailed study of the virus engaging targeted quasi-species analysis to characterize distinguishing motifs associated with NCI, and to study the relationship to viral subtype and the relationship of viral drug resistance in different compartments to NCI. The research team is comprised of internationally recognized HIV, neuro-AIDS and molecular virology experts from the University of Maryland, leading neuro-AIDS scientists from the University of California San Diego HIV Neurobehavioral Research Center (UCSD/HNRC), and local research investigators from the Institute of Human Virology-Nigeria (IHV-N) and affiliates in Nigeria. Additionally an extensive repository of viable peripheral blood cells, DNA and plasma will be collected for future studies.

Public Health Relevance

The public health implications are that a high frequency of impairment in the ability of people to think clearly due to HIV infection can have adverse effects on treatment success. The current project will provide information on how frequently this impairment occurs and to understand how the virus causes this impairment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH086356-02
Application #
8102804
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Joseph, Jeymohan
Project Start
2010-07-01
Project End
2015-02-28
Budget Start
2011-05-01
Budget End
2012-02-29
Support Year
2
Fiscal Year
2011
Total Cost
$661,621
Indirect Cost
Name
University of Maryland Baltimore
Department
Neurology
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Jumare, Jibreel; El-Kamary, Samer S; Magder, Laurence et al. (2018) Body Mass Index and Cognitive Function among HIV-1 Infected Individuals in China, India and Nigeria. J Acquir Immune Defic Syndr :
Jumare, Jibreel; Sunshine, Sara; Ahmed, Hayat et al. (2017) Peripheral blood lymphocyte HIV DNA levels correlate with HIV associated neurocognitive disorders in Nigeria. J Neurovirol 23:474-482
Royal 3rd, Walter; Cherner, Mariana; Burdo, Tricia H et al. (2016) Associations between Cognition, Gender and Monocyte Activation among HIV Infected Individuals in Nigeria. PLoS One 11:e0147182
Akolo, Christopher; Royal 3rd, Walter; Cherner, Mariana et al. (2014) Neurocognitive impairment associated with predominantly early stage HIV infection in Abuja, Nigeria. J Neurovirol 20:380-7
Davis, Matthew J; Khan, Adnan; Royal 3rd, Walter (2013) Progressive multifocal leukoencephalopathy as the first manifestation of occult sarcoidosis: case report and review of the literature. Neurologist 19:26-9
Joseph, Jeymohan; Achim, Cristian L; Boivin, Michael J et al. (2013) Global NeuroAIDS roundtable. J Neurovirol 19:1-9
Guo, Ming; Bryant, Joseph; Sultana, Shireen et al. (2012) Effects of vitamin A deficiency and opioids on parvalbumin + interneurons in the hippocampus of the HIV-1 transgenic rat. Curr HIV Res 10:463-8
Royal 3rd, Walter; Cherner, Mariana; Carr, Jean et al. (2012) Clinical features and preliminary studies of virological correlates of neurocognitive impairment among HIV-infected individuals in Nigeria. J Neurovirol 18:191-9
Siskin, Gary P; Haskal, Ziv J; McLennan, Gordon et al. (2011) Development of a research agenda for evaluation of interventional therapies for chronic cerebrospinal venous insufficiency: proceedings from a multidisciplinary research consensus panel. J Vasc Interv Radiol 22:587-93
Sultana, Shireen; Li, Huifen; Puche, Adam et al. (2010) Quantitation of parvalbumin+ neurons and human immunodeficiency virus type 1 (HIV-1) regulatory gene expression in the HIV-1 transgenic rat: effects of vitamin A deficiency and morphine. J Neurovirol 16:33-40